Modulators of cystic fibrosis transmembrane conductance regulator

Patent metadata

Field	Value
Publication number	US-12168009-B2
Application number	US-202217865220-A
Country	US
Kind code	B2
Filing date	Jul 14, 2022
Priority date	Oct 6, 2014
Publication date	Dec 17, 2024
Grant date	Dec 17, 2024

Abstract

The present invention features a compound of formula I:

or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , W, X, Y, Z, n, o, p, and q are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present invention also features pharmaceutical compositions, method of treating, and kits thereof.

First claim

The invention claimed is:

1. A compound of formula Ia:

a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, independently for each occurrence:
Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, or a C3-C10 cycloalkyl ring;
X is O or NR;
Y is CRR, CO, O, S, SO, SO 2 , S(O)NH or NR;
R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C1-C6 alkyl; C1-C6 fluoroalkyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; C2-C6 alkenyl; C2-C6 alkynyl; (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; C1-C6 alkyl; C1-C6 fluoroalkyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; C2-C6 alkenyl; C2-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 may form a ═CH 2 or ═O group;

R 3 is halo; CN; CO 2 R; C1-C6 alkyl; C1-C6 fluoroalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 3 may form a ═CH 2 or ═O group;

R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 ; C1-C6 alkyl; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
n is 0, 1, 2 or 3;
o is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.

2. The compound, deuterated derivative, or salt of claim 1 , wherein ring B is phenyl, pyridyl, pyridine-2 (1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4 (1H)-one, pyrrolidinone, or quinoline.

3. The compound, deuterated derivative, or salt of claim 1 , wherein ring B is selected from

4. The compound, deuterated derivative, or salt of claim 1 , wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, piperidine, or dihydroindene.

5. The compound, deuterated derivative, or salt of claim 1 , wherein ring C is

6. The compound, deuterated derivative, or salt of claim 1 , wherein Y is O.

7. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH 2 .

8. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(C1-C6 alkyl).

9. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(CH 3 ).

10. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(CH 2 CH 3 ).

11. The compound, deuterated derivative, or salt of claim 1 , wherein R 1 is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, or thiophene ring, wherein all rings may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH 2 OH, CH 2 OCH 3 , CN, CO 2 H, amino, amido, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, or a (C1-C8 alkyl)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

12. The compound, deuterated derivative, or salt of claim 1 , wherein R 1 is selected from CH 3 , Cl, F, CN, OCH 3 , CF 3 , CH 2 CH 3 , tBu, CH(CH 3 ) 2 ,

13. The compound, deuterated derivative, or salt of claim 1 , wherein R 2 is halo, OH, CN, azide, amino, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, C3-C10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR; or a (C1-C8 alkyl)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.

14. The compound, deuterated derivative, or salt of claim 1 , wherein R 2 is selected from Cl, F, OH, CN, N 3 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CH 2 OH, CH 2 CH 3 , CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCF 3 , OCHF 2 , OCH(CH 3 ) 2 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

and CO 2 H.

15. The compound, deuterated derivative, or salt of claim 1 , wherein R 3 is selected from halo, CN, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, and C3-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.

16. The compound, deuterated derivative, or salt of claim 1 , wherein R 3 is selected from Cl, F, CN, CH 3 , OCH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 CH 3 , OCH 2 CH 3 , CH 2 OCH 3 , CH(CH 3 ) 2 , CCH, CO 2 CH 3 , tBu,

17. The compound, deuterated derivative, or salt of claim 1 , wherein o is 0.

18. The compound, deuterated derivative, or salt of claim 1 , wherein o is 1.

19. The compound, deuterated derivative, or salt of claim 1 , wherein n is 0.

20. The compound, deuterated derivative, or salt of claim 1 , wherein n is 1.

21. The compound, deuterated derivative, or salt of claim 1 , wherein n is 2.

22. The compound, deuterated derivative, or salt of claim 1 , wherein p is 0.

23. The compound, deuterated derivative, or salt of claim 1 , wherein p is 1.

24. The compound, deuterated derivative, or salt of claim 1 , wherein p is 2.

25. The compound, deuterated derivative, or salt of claim 1 , wherein ring B is phenyl.

26. The compound, deuterated derivative, or salt of claim 1 , wherein ring B and ring C ar

Assignees

• Vertex Pharma

Inventors

• Miller Mark Thomas
• Anderson Corey
• Arumugam Vijayalaksmi
• Bear Brian Richard
• Binch Hayley Marie
• Clemens Jeremy J
• Cleveland Thomas
• Conroy Erica
• Coon Timothy Richard
• Frieman Bryan A
• Grootenhuis Peter Diederik Jan
• Gross Raymond Stanley
• Hadida-Ruah Sara Sabina
• Khatuya Haripada
• Joshi Pramod Virupax
• Krenitsky Paul John
• Lin Chun-Chieh
• Marelius Gulin Erdogan
• Melillo Vito
• Mccartney Jason
• Nicholls Georgia Mcgaughey
• Pierre Fabrice Jean Denis
• Silina Alina
• Termin Andreas P
• Uy Johnny
• Zhou Jinglan

Classifications

• C07D213/64

  attached in position 2 or 6 · CPC title

• C07D209/49

  and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters · CPC title

• C07D209/18

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/34

  One oxygen atom · CPC title